Pharmaceutical Biotechnology Downstream processing with ...
32
Pharmaceutical Biotechnology Downstream processing with centrifuges and package units from GEA Westfalia Separator engineering for a better world GEA Mechanical Equipment
Transcript of Pharmaceutical Biotechnology Downstream processing with ...
Pharmaceutical Biotechnology
Downstream processing with centrifuges and package units from GEA Westfalia Separator
engineering for a better world GEA Mechanical Equipment
2
Quality in its Purest Form
Downstream processing technology
Aseptic process management, optimum cleaning
capability, closed product handling, reliable
compliance with GMP requirements, gentle product
treatment, efficient recovery of active ingredients
and reliable scale-up – the requirements of pharma-
ceutical biotechnology are high. With separators
designed specifically for this sector, GEA Westfalia
Separator Group stands for reliable compliance
with these requirements.
GEA Westfalia Separator Group built the first
centrifuge in Oelde, Westphalia in 1893. Since
then, the company has been instrumental in the
advancement of mechanical separation technology.
Today, it is a key technology in the recovery of active
pharmaceutical ingredients with substantial potential
for optim ising production processes and products.
A critical factor underlying the success of the
company in pharmaceutical biotechnology is its
ability to swiftly translate new developments into
marketable processes and systems which fully
meet the complex requirements of biotechnological
processes. The basis for this is decades of experience
in the construction and production of separators
for the pharmaceutical industry, picking up on
new research findings and the implementation of the
latest design and production processes. Using this
approach, GEA Westfalia Separator Group has
developed numerous innovative improvements to
separating processes and brought them to market
world-wide by applying first-class engineering.
3
Efficient, reliable and economical
GEA Westfalia Separator Group supports new
developments in the branch from the outset through
continuous cooperation with universities, research
institutes and industry. In this way, a rapid and
individual response to current customer needs is
assured at all times. With stand-alone machines or
package units which guarantee a high yield of
valuable substances and which operate trouble-free,
efficiently, reliably and economically throughout
a long service life. Convince yourself!
4
Enzymes
Process acceleration with biocatalysts
Enzymes are complex organic protein compounds
located in every living cell, where they are produced.
They accelerate organic processes such as the
breakdown of starch, protein, fat or sugar as
catalysts, i. e. without being expended themselves.
These valuable proteins are known to industry
as esteemed helpers. The separators and decanters
from GEA Westfalia Separator Group ensure that
the intracellular and extracellular enzymes are
separated undamaged and in high concentrations.
Production of intracellular enzymes
Glucose isomerase is an example of an enzyme which
converts glucose into fructose and is highly
significant in the starch industry. The enzyme is
produced and remains in the cells of the employed
micro-organisms. To process it, the liquid phase of the
fermentation broth is separated by centrifuging after
fermentation. The concentrated microorganisms are
treated further after centrifuging. The cell walls are
broken down. Depending on the consistency of the
suspension, it is diluted before the cell fragments are
separated by continuously operating separators.
Production of extracellular enzymes
Separators and decanters from GEA Westfalia
Separator Group are predestined for the optimum
treatment of washing powder enzymes. Carefully
purified and sterilised air is injected into a fermenter
equipped with an agitator. The air bubbles are
distributed in the nutrient solution, which
is composed of carbohydrates, protein, growth agents
and nutrients. This is sterilised, heated to an optimum
temperature and then inoculated with the purified
culture of a nonpathogenic microorganism. The
microorganisms nourish themselves by converting
the substances and simultaneously produce the
enzymes. These are then excreted to the fermentation
broth. After fermentation, the microorganisms are
separated by adding a flocculent and centrifuging
with separators and decanters. Succeeding stages of
washing and polishing with centrifuges further
increase the yield and the purity of the enzymes.
5
1 Aeration
2 Microorganism
3 Substrate
4 Fermentation
5 Rotary brush strainer
1 Aeration
2 Microorganism
3 Substrate
4 Fermentation
5 Flocculents
6 Rotary brush strainer
6 Separator
7 Liquid (waste)
8 Water / buffer
(washing liquid)
9 Biomass
7 Separator
8 Decanter
9 Biomass
10 Water / buffer
(washing liquid)
11 Extracellular liquid
1
2
3
4 5
6
7
8
9
106
11
13
12
10 Cell disruption
11 Cell debris to disposal
12 Intracellular liquid
13 Further processing
12 Polishing
13 Extracellular liquid for
further processing
14 Biomass to disposal
1
1
2
2
3
3
4
4
5
6
5
7
8
8
9
10
109
7
11
11
12
12
13
14
13
14
Intracellular enzymes
Extracellular enzymes
6
Microbial Food Cultures
Microbial food cultures can be subdivided into
starter cultures and probiotic products; they are
used in many segments of the food industry.
Starter cultures are now an established part of the
food, medical product and animal feed industries.
They are responsible for predictable and reproducible
product quality and thus for controllable production
processes. Probiotic products are also becoming
more and more important, mainly as a result of
their beneficial health characteristics. Sterilisable
separators are becoming more and more important
for recovering such products; they can be used in a
variety of ways and enable the yield and vitality of
the cultures to be enhanced.
Cultivation, processing, harvesting
The production of starter cultures can be divided into
two sections. After cultivation in fermenters, the
bacteria must be processed and separated from the
fermentation solution. This consists of the nurtured
lactobacilli and the remainder of the nutrient
solution including the produced lactic acid. Firstly,
the micro-organisms are separated and concentrated
1 Nutrient solution
2 Aeration
3 Freeze-dried starter cultures
4 Seed fermenter
5 Pre-fermenter
6 Main fermenter
7 Nozzle separator
8 Waste
9 Concentrate
10 Freeze drier
11 Water (waste)
12 Packaging
13 Pelletizer
14 Cold store
1
2
3
4
5
6
7
8
9 10
11
12
1314
7
from the liquid phase. Nozzle and self-cleaning disc
separators in steam-sterilised design are available
for this step of the process. The concentrated
lactobacilli then pass to a freeze drier. Finally, the
cultures are packaged under oxygen exclusion and
stored at low temperatures. This retains their activity
for months before they are processed, e. g. as “live
cultures” in probiotic yoghurts.
Sterility and careful treatment
The careful treatment of the living microorganisms,
sterility and a high separation efficiency are
prerequisite to the economical, reliable and efficient
processing. The separators from GEA Westfalia
Separator Group employed in this production process
are therefore equipped with hydrohermetic product
feed systems which minimise the shear forces when
the product enters the bowl and therefore guarantee
the high vitality of the cells.
8
Vaccines
Protection against germs
Vaccines are medicines which immunise human or
animal organisms against diseases. The organism
to be protected is repeatedly exposed to small
quantities of antigens (vaccines) or antibodies in
the form of a serum. This achieves immunity.
Live vaccines
One means is therapy with live vaccines. These are
germs with weakened virulence or closely related to
pathogenic germs and are therefore antigens, but
without the pathogenic effects. They are bred from
less pathogenic mutations of virulent germs, which
are suitable for the production of vaccines.
Process of vaccine manufacturing
When a suitable virus strain has been chosen, it is
isolated in ampoules and stored at -192 °C in liquid
nitrogen. Breeding is then conducted starting with
the pre-fermenter and continuing in the main
fermenter. The fermentation process is supplemented
by a nutrient solution. The nutrients are dissolved in
the nutrient tank and added to the fermentation
process after filtration. The cells are then separated
from the clear phase by centrifuging. The raw vaccines
pass into the mixing vessel, where their immunogenity
is increased by the addition of adjuvants, stabilisers
and preservatives.
Live vaccines• Measles• Mumps• Rubella• Yellow fever• Chickenpox• BCG (= tuberculosis vaccine)• Typhus• Human rotaviruses• Whooping cough (pertussis)
1 Aeration
2 Starter culture
3 Dried nutrients
4 Water
5 Pre-fermenter
6 Nutrient tank
7 Virus culture
1
2
4
3
5
6
7
8
9
10
11
7
12
13
14
15
16
17
18
19
20
21
8 Filter press
9 Nutrient solution
10 Main fermenter
11 Additives
12 Separator
13 Mixing tank
14 Raw vaccine
15 Liquid
16 Freeze dryer
17 Steam
18 Continuous sterilizer
19 Effluent
20 Water (waste)
21 Vaccine
9
Non-live vaccines
In serum therapy, the infected organism is
supplied with the sera produced with the antibodies
of immunised individuals. Sera are gained by
multiplying bacteria in a suitable nutrient solution.
The serum produced during fermentation is excreted
by the cells into the fermentation solution. The serum
is isolated by separating the biomass in centrifuges
and by further stages of processing in the clarification
phase.
An aseptic process is essential in the production of
vaccines and sera.
Non-Live vaccines• Influenza• Cholera• Bubonic plague• Hepatitis A or hepatitis B • Whooping cough (pertussis)• Tetanus• Diphtheria• Pneumococcal bug
1 Aeration
2 Starter culture
3 Dried nutrients
4 Water
5 Pre-fermenter
6 Nutrient tank
7 Virus culture
8 Filter press
9 Nutrient solution
10 Main fermenter
11 Separator
12 Biomass
13 Killing tank
14 Serum for further
production
15 Biomass to disposal
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
10
Hormones / Insulin
Separation technology for human medicine
Hormones are chemical messengers which have a
regulating effect on the metabolism and organ
activity. In collaboration with the nervous system,
they co-ordinate all bodily functions. A complicated
control mechanism ensures a harmonic interaction
of the bodily functions. The separation technology
of GEA Westfalia Separator Group plays an important
part in the production of hormones, e. g. insulin.
Diabetes
Diabetes is a metabolic disorder. Diabetics can no
longer adequately utilise glucose, which is conveyed
by the blood to all cells of the body. The hormone
insulin has a key function in this. Amongst other
functions, it operates as a “door opener” for glucose
molecules when they enter cells. Around 150 million
people worldwide now suffer from this metabolic
disorder. They must inject supplementary insulin daily
to prevent serious cardiovascular or renal diseases.
In the service of human medicine
Separators from GEA Westfalia Separator Group play
an important part in the production process. Nozzle
separators operate in the depicted process, in which
the solid material is extracted continuously in a
constant concentration. The biosynthetic production
of human insulin is conducted by bacteria or yeasts.
After fermentation, or the conversion of the chemical
raw materials by the micro-organisms, the biomass is
extracted by a nozzle separator. In further stages, the
active ingredient is washed and concentrated.
GEA Westfalia Separator Group machines are also
employed in the succeeding crystallisation stages,
for example GEA Westfalia Separator hycon and
chamber separators.
1 Aeration
2 Microorganism
3 Substrate
4 Fermentation
5 Nozzle separator
6 Liquid (waste)
7 Biomass
8 Water / buffer
(washing liquid)
9 Cell disruption
10 Cellular liquid with
cell debris (waste)
11 Solids
12 Water / buffer
13 Washing liquid
14 Inclusion bodies
15 Protein folding
16 Precipitation of
foreign proteins
17 Separator
18 Crystallization of insulin
19 Chamber bowl centrifuge
20 hycon
21 Clear phase to waste
22 Insulin crystals to freeze dryer
1
2
3
4
5 5
5 5
6
7
8
910
1112
6 6
11
13
14
15 16 17 11 18
19
20
21
21
22
22
Example insulin based on E.Coli
11
How sugar metabolism works
The pancreas excretes
insulin into the blood-stream.
Insulin helps to convey glucose into the cells: it opens the cells.
Glucose,
blood sugar.
Glucose is oxidised in
the cells to generate
energy.
1 Aeration
2 Microorganism
3 Substrate
4 Fermentation
5 1st stage nozzle separator
6 Clear phase
1
2
3
4
5
6 66
7 7
8 9
10 11
12
13
14 15 1617
18
18
19
Example insulin based on yeast
7 Concentrate
8 Water
9 Additive
10 2nd stage nozzle separator
11 Polishing separator
12 To waste
13 Chromatography column
14 1st stage crystallization
15 Chamber bowl
centrifuge
16 2nd stage crystallization
17 hycon
18 Clear phase to waste
19 Insulin crystals to freeze dryer
9 9
12
Pharmaceutical Proteins
Genetically modified bioproducts
Biotechnological processes can be characterised as
processes employing genetically modified micro-
organisms. These are able to produce biological
products which they would never have created in
their natural form. The modified DNA chain and
therefore the genetically manipulated heredity
factor is multiplied by fermentation of the micro-
organisms. The DNA chain with the modified gene
and the substances which it produces develop
simultaneously. The desired cell products may be
contained intra or extracellularly.
1 Aeration
2 Microorganism
3 Substrate
4 Fermentation
5 Separator
6 Water / buffer
(washing liquid)
7 Extracellular liquid
containing soluble
protein
8 Water / buffer
9 Biomass
10 Cell disruption
11 Cellular liquid with cell
debris (waste)
12 Liquid (waste)
13 Inclusion bodies
14 Further processing
15 Intracellular liquid
16 Solids to disposal
1
2
3
4
5 5
6
7
89
10
5 5
5
5
6
11
6
12
12 13
14
11
10
14
15
16
Extracellular products
Inclusion bodies products Intracellularproducts
13
Extracellular products
After fermentation, the micro-organisms are extracted
by continuously operating separators. To increase the
yield, the solid material is washed and extracted again
by centrifuging. The clarified phases of the two stages
are mixed and fed to further stages of the process.
All material streams leaving this enclosed process
must be sterilised at at least 121 °C. To keep the process
as simple as possible, the biomass is killed directly
after fermentation in the fermenter either by heat or
by chemical methods. Completely enclosed, steam
sterilised centrifuges are employed in this process
and can be connected to the other equipment in a
sterile manner.
Intracellular products and inclusion bodies
In intracellular processes, it is differentiated whether
the desired product is contained in the intracellular
liquid or in so-called inclusion bodies. In contrast to
extracellular bioproduction, the clarified phase leaves
the process here and the biomass is processed. The
washed and concentrated biomass is homogenised,
i.e. the cells are broken down and the intracellular
liquid and the inclusion bodies are released. These
are separated from the cell fragments, washed and
concentrated in further stages of the process by
centrifuges from GEA Westfalia Separator Group. For
intracellular products gained from the cell liquid,
the solids are extracted by continuously operating
separators.
14
1 Aeration
2 Microorganism
3 Substrate
4 Fermentation
5 Separator
6 Solids to disposal
7 Depth
filtration
8 Microfiltration
9 Protein solution for
further processing
1
2
3
4
5
67 8
9
Mammalian Cell Cultures
Cultures of the future
The cultivation of mammalian cell cultures
is becoming increasingly interesting for the
pharmaceutical industry. With these cells, proteins
can be produced in their effective form (quartiary
structure). In comparison with production by
micro-organisms (bacteria / yeasts), downstream
stages of the process can be substantially reduced.
In addition, risks such as infections in the
production of human proteins can be avoided.
Optimisation of the production process
In this process, particular attention must be paid to
the effects of extraneous influences such as the shear
forces on the behaviour and productivity of the
cells. Due to this circumstance, the machines were
optimised to reduce the shear forces on the cells.
This process is therefore gaining significance for
industry.
The “hydrohermetic inlet” developed by GEA Westfalia
Separator Group reduces the shear forces to a
minimum. This has been tested and published
in cooperation with the University of Bielefeld.
Typical cell cultures which are processed are CHO,
BHK, hybridoma and insect cells.
15
16
Human Blood Plasma Fractionation
Progress with blood
Blood is a special liquid. Is there actually anything
more valuable? The basis of all human life is
also the foundation for a globally operating
industry. Whereas state institutions and aid
organisations generally use and pass on whole
blood, many industrial companies have specialised
in fractionation. Therapy with blood components
to explicitly combat numerous illnesses long ago
developed from simple blood transfusions.
Valuable: plasma proteins
Fractionation is the separation of the proteins in the
plasma phase by physical and chemical processes.
They are based on changes in the three parameters
temperature, alcohol concentration and pH value,
which affect the solubility of the proteins in water.
Human blood consists of a red phase and the clear
plasma phase. The red phase, about 40 percent of the
blood, is separated by special centrifuges in the donor
bag. The plasma is deep frozen after extraction and
is processed by fractionation equipment. Only
about 5 percent of the plasma consists of the valuable
components, which must be fractionated. The
remainder is water and electrolytes.
Therapy with blood components
Many valuable substances can be extracted from the
proteins. The cryoprecipitate, the clotting preparation
“Factor VIII concentrate” and the prothrombin
complex (PPSB) can be gained from the fresh plasma
straight after thawing. The remaining plasma then
passes to the ethanol fractionation by the Cohn process,
where the individual fractions such as fibrinogen,
gamma globulin, aplha and beta globulin and albumin
23
1
23 4
44
4
5
6
7
4 4
14
15
16
17
18
22 24
17
are precipitated. The plasma protein particles are used
to prevent and treat bleeding, to control bleeding
during operations, for various infectious diseases, for
protein deficiency, malnutrition and to increase the
proportion of blood plasma. After fractionation, the
proteins are treated by various specific methods
before they are available for clinical purposes.
Demands on the separating technology
Fractionation by the Cohn process is conducted by
reliable separators with cooled bowls and housings.
The maintenance of a temperature range of -3 to -6 °C
is important for the process. Chamber separators of
type BKB are employed for this purpose.
The separators of the latest generation are self-
cleaning separators of the GEA Westfalia Separator
hycon type (BSH 30), with which manual handling of
the solids is no longer necessary (see page 28).
1 Collecting of plasma
2 Cold store
3 Thawing (temp. appr. 0 °C)
4 Protein concentration
5 Solids
6 Buffer
7 Washing (temp.appr. 0 °C)
8 Factor VIII concentrate
9 Liquid (waste)
10 Re-suspension with
buffer (temp. appr. 0 °C)
11 Freeze drying
12 Water (waste)
13 Cryo precipitate
14 Alcohol
15 Regulation
16 Protein precipitation
(Alcohol content = 8%,
temp. = -3 °C, pH = 7.3
17 Fraction I
(Fibrinogen)
18 Protein precipitation
(Alcohol content = 25%,
temp. = -5 °C, pH = 6.8
19 Protein precipitation
(Alcohol content = 40%,
temp. = -5 °C, pH = 5.9
20 Fraction IV
( - and - Globulin to
disposal)
21 Protein precipitation
(Alcohol content = 40%,
temp. = -5 °C, pH = 4.8
22 Protein precipitation
(Alcohol content = 8%,
temp. = -5 °C, pH = 5.1
23 Fraction III
( - Globulin to disposal)
24 Protein precipitation
(Alcohol content = 25%,
temp. = -6.5 °C, pH = 7.3
25 Fraction II
( - Globulin)
26 All separators / bowls cooled
with alcohol / water of 20 °C
27 Liquid phase to waste
28 Fraction V (Albumin)
25 28
8
9 10
9
1112
13
19 21
20
26 27
18
respect, and has been continuously improved in
cooperation with the customer. This documentation
standard now covers almost 100 percent of GMP
requirements. Individual customer requirements can
be quickly and easily implemented as a result of the
”open” documentation structure. Flexibility is
therefore a strong point of the documentation.
Documented qualification for pharmaceutical
machinery
As stipulated by GMP and other rules, the qualification
and validation of pharmaceutical machinery have a
high priority. Qualification designates the documented
proof of the execution and functionality of a machine.
Validation refers to the reproducible, reliable setting
of the processes. In this, it is particularly important
to work with qualification plans and documents
approved by the user. Within the machine qualification,
GEA Westfalia Separator Group can execute the
design qualification (DQ), installation qualification
(IQ) and operating qualification (OQ) in the course of
the FAT. If requested, the OQ can be conducted in the
course of the SAT, with support at the first production.
Additional profit by way of synergy effects
Most of the qualification work, which is normally
the responsibility of the client, is provided by
GEA Westfalia Separator Group as a service. The
structured procedure at GEA Westfalia Separator Group
provides major advantages for the future
operator: it considerably reduces the amount of
qualification work and also benefits from numerous
synergy effects.
GMP stands for “Good Manufacturing Practice”. The
rules specify that the quality of a product cannot
be assured exclusively by a final inspection.
Specific measures before, during and after production
are required. The focus is on the detailed
documentation of each relevant production stage
or test being carried out.
All relevant departments are incorporated
in the GMP team
The GMP documents can therefore quickly assume a
volume of 400 to 800 pages. Suppliers without GMP
experience enter this ”collection of materials” into
production, manufacture and then attempt to put
together the required documents. However, a better
solution is if the supplier works in line with GMP
right from the very beginning. GEA Westfalia
Separator Group has set up a separate GMP group
comprising specialists from all relevant departments;
ranging from project management, design, production,
plant construction, measuring and regulating technology,
right through to quality assurance and acceptance.
The aim of the project is to reduce the amount of
qualification work for the customer and also to
implement his specifications as effectively as possible
in project processing.
Documentation standards cover almost
100 percent of GMP requirements
A documentation standard that is consistent with
GMP has been developed as a major module in this
Good Manufacturing Practice
19
Separators for Pharmaceutical Biotechnology
Machines for all applications
GEA Westfalia Separator Group offers an extensive
selection of separators for biotechnology with varying
production capacities and designs, from the
Machine type Product throughput (depending on
the product and process in l/h)
Applications
Self-cleaning separators
FSC 6* / PSC 6 100 – 200
Mammalian cell cultures,
microbial food cultures, enzymes,
pharmaceutical proteins,
hormones
FSC 15* / PSC 15 250 – 500
FSC 20* / PSC 20 500 – 1000
FSE 80* / PSE 80 1500 – 3000
FSE 170* / PSE 170 3000 – 6000
FSE 300* / PSE 300 5000 – 15.000
Steam-sterilized, self-cleaning separators
CSC 6 100 – 200 Aseptic processes, vaccines and sera,
mammalian cell cultures,
microbial food cultures,
pharmaceutical proteins,
hormones / insulin
CSC 15 250 – 500
CSC 20 500 – 1000
CSE 80 1500 – 3000
CSE 100 1800 – 3700
CSE 170 3000 – 6000
Steam-sterilized separators with viscon® nozzles
CFC 15 300 – 600 Aseptic processes, microbial food
cultures, enzymes, pharmaceutical
proteins, hormones / insulin
CFA 65 3000 – 6000
Steam-sterilized separators with nozzles
CFD 130 3000 – 8000 Aseptic processes, microbial food
cultures, mammalian cell culturesCFE 300 10.000 – 20.000
Chamber separators
PKB 25 300 – 600 Hormones / insulin, pharmaceutical
proteinsPKB 45 500 – 1000
BKB 28 300 – 600 Human blood plasma fractionation
BKB 45 500 – 1000
Hyperconcentrators – hycon
PSH 30 500 – 1500 Aseptic processes, hormones / insulin,
pharmaceutical proteinsCSH 30 500 – 1500
BSH 30 500 – 1500 Aseptic processes,
human blood plasma fractionation
Solid wall disc separators
FTC 1* 30 – 60 Research establishments, labs
Self-cleaning separators
Pathfinder PSC 1 / PSC 5 / PSC 8* 15 – 300 Research establishments, labs
FSD 1* 20 – 50 Research establishments, labs
smallest nozzle separator with GEA Westfalia
Separator viscon® technolgy right up to the largest
steam-sterilizable centrifuge in the world – the CFE 300.
* This design will be offered without polished surfaces and documentation.
20
Hydrohermetic Inlet
Gentle product feed
Gentle and careful handling of the product is
extremely important in biotechnology to achieve
a high degree of vitality and protein activity
and to minimise changes. To feed all fluid
products carefully into the rotating bowl, all
separators from GEA Westfalia Separator Group
for the pharmaceutical sector are equipped with a
hydrohermetic inlet.
This inlet system prevents shear forces when the
product enters the bowl. The product is introduced
beneath the level of the liquid. It allows the level of
the liquid to reach the axis of rotation, beneath which
the product is gently introduced into the filled bowl
and accelerated. The hydrohermetic inlet, developed
and patented by GEA Westfalia Separator Group,
has been successfully tested on mammalian cell
cultures and published by the University of Bielefeld.
21
GEA Westfalia Separator viscon®
Gentle discharge of solids – no problem
Great advances have been made in recent years in
the field of centrifuging for concentration with
nozzle separators. With the development of the
viscosity-controlled nozzle (viscon®), the
inconvenient adjustment of the separator
parameters (ejection time) to changing inlet
conditions has become unnecessary. This achieves
constant solid discharge concentrations. The nozzle
separators represent the state-of-the-art in the field
of the treatment of microbial food cultures, hormones,
pharmaceutical proteins etc, last but not least due
to viscon®.
Increased survival rate
In contrast to conventional nozzle separators, the
nozzles of the viscon® system are not located at the
edge of the bowl, but at a smaller circumference in
the bowl top. Pressures of up to 250 bar prevail at the
periphery of the bowl, whereas the pressures are
substantially lower at the centre of the bowl. This
means that the separated cells are subjected to much
lower shear forces. The introduction through the
hydrohermetic inlet and the discharge through the
viscon® nozzles increase the activity of the separated
cells. The result: the end product is more valuable and
can be employed more economically.
High mass flow
rate at the inlet
Low mass flow
rate at the inlet
®
®
GEA
®
®
GEAP
P
22
Ejection with GEA Westfalia Separator hydrostop
Extremely fast, precise and flexible
With the hydrostop system, GEA Westfalia
Separator Group has provided an ejection
system which can be adjusted precisely and repro-
ducibly to specific requirements with regard
to the concentration of solids. This patented
ejection system makes it possible to optimise the
ejection sequence to the shortest time. The
hydrostop system reduces the actual ejection time
to less than 1/10 of a second and allows partial
ejection every thirty seconds.
Extremely precise even with the smallest volumes
The great disadvantage of older ejection systems was
that they were substantially slower and less precise.
The volume and thereby the concentration of the
solids fluctuated widely. No form of control was
possible. The hydrostop system ensures that even
small volumes from 1.5 to 2 litres can be ejected
reproducibly with an error margin of less than 10
percent. This innovative technology allows precise,
fast ejection and therefore substantially increased and
higher quality yields.
seconds
GEA
23
Ejection with Metering Pistons
Precisely metered discharge volumes
The fundamental idea of the control system is to
inject a precisely metered volume of opening water
with a metering system for partial ejection.
Precise ejected quantities can be achieved in this
way. The advantage in comparison with the
hydrostop system is the low required operating
water pressure of just 1.5 bar.
In the pharmaceutical industry, high-purity water
from ring systems is often employed as the operating
water. Pressures of 1.5 to 2 bar usually prevail here.
For this reason, separators from GEA Westfalia
Separator Group with pneumatically-operated
external metering pistons have a proven track record.
The volume of opening water can be varied with an
adjusting screw. The metering device is filled with
water through the inlet valve. Compressed air is then
injected through the valve into the lower chamber of
the metering device. After the opening water valve
has been operated, the air pressure applied to the
piston of the metering device injects the adjusted
volume of water into the opening chamber. The air
pressure for the metering device should be 4 – 4.5 bar.
A pressure converter installed in the metering device
ensures correct ejection, overcoming the resistance
of the piping, valve and injection chamber.
24
Steam Sterilising – SIPCleaning Capability – CIP
Securely sterile and clean
In some processes, e.g. in the production of vaccines
and sera, a strictly aseptic process is required. The
separator must not only be easy to clean, but is also
a part of a sterile, completely closed system. Apart
from guaranteeing the agreed performance
parameters, GEA Westfalia Separator Group also
grants a so-called sterile guarantee on the employed
sterile separators.
A validation of the sterilising capability of a
separator package unit according to the FDA
specifications (Food and Drug Administration) was
tested successfully and certified by the “Gesellschaft
für biotechnologische Forschung” (GBF) in Brunswick.
This concept has proven favourable in more than
600 steam-sterilised separators installed world-wide.
Sterile with steam
SIP (Sterilisation-in-place), for example, this applies
to our self-cleaning disc separators with hydrohermetic
inlets in a special steam-sterilised design. Sterilising
is conducted with the separator stopped with hot
steam under pressure at a temperature of over 121 °C.
The sterilising period is dependent on the type of
bacteria and the cell count. After sterilising, the
separator is filled with sterile air for cooling and
blanketing until the next production run. Sterilisation
prevents cross-contamination of different fermen-
tation products which are processed by the same
separator. It also prevents toxic bacteria or living
germs from escaping to the exterior and endangering
people (biocontainment). This has also been proven
and published by the UCL (University of London).
Absolutely clean with CIP
Chemical CIP cleaning (CIP = cleaning-in-place)
cleans process lines without the need to dismantle
or open individual machines. Apart from hot
water, 2 percent sodium hydroxide solution
at a temperature of up to 80 °C is used as the
cleaning liquid. This is circulated until all organic
sediments have been dissolved. 0.5 percent nitric
acid solution at a temperature of up to 80 °C is used
to dissolve anorganic sediments. The last stage
of the CIP chain is rinsing with high-purity water.
25
Good design
Apart from the specified steps of cleaning, a good
machine design is very important. This particularly
includes a good draining capability, the prevention
of dead spaces, easily cleaned, smooth surfaces
and an optimum wetting of the surfaces in contact
with the product by the CIP media. GEA Westfalia
Separator Group achieves this by installing spray
nozzles at different points in the separator and
ensuring the wetting by an uranine test, the employ-
ment of separators and system components with
little dead space such as laser-welded spacers and
diaphragm valves, surface roughness of Ra ≤ 0.8 µm
or better and a minimum pipe inclination of < 2 percent.
Automatically safe
GEA Westfalia Separator Group not only supplies
centrifuges, but also fully automatic CIP systems. The
cleaning cycle is controlled by a programmable logic
controller. The program sequence for cleaning can
be adapted according to the local requirements. The
volume of cleaning agents is metered by the installed
pumps. A conductivity sensor adjusts and monitors
the concentrations of the media in the respective
cleaning circulation systems.
26
GEA Westfalia Separator hycon
Design for clean room applications
When separators are installed in clean rooms,
special attention must be paid that no particles are
emitted to the surroundings and that the machinery
can be easily cleaned. At GEA Westfalia Separator
Group, this is achieved by direct frequency converter
drives (no centrifugal friction clutches), stainless
steel control cabinets and the integration of
machine components such as pilot valves and
pressure reducing valves in a valve cabinet. The latest
development by GEA Westfalia Separator Group is
the design as a two-room concept with hycon.
Two-room concept
To achieve a sterile process, the drive section (drive
system and motor) and the process room (bowl and
solids discharge) are sealed hermetically from each
other by gas-lubricated slide ring seals. The design is
such that the respective components are located apart
from each other. This so-called two-room concept is
implemented by the suspended bowl and solids discharge
in the clean room. This precludes contamination of the
process room by the drive equipment.
27
Sterile handling
Cooling requirements
SIPCIP
Two-room concept Cooling with liquid nitrogen
Pneumatically controlled discharge Temperature range +135 °C (SIP) / -29 °C
Cleaning-in-place Sterilisation-in-place
Economical clean room conditions
The hycon achieves the highest concentrations of
solids in an aseptic process. It unifies the advantages
of chamber separators and self-cleaning separators,
thereby completely fulfilling the high requirements
of the pharmaceutical industry. The hermetic isolation
of the product-contacting and the mechanical sections
allows the user to create economical clean room
conditions. A sterile process is also achieved by a fully
closed, steam-sterilised system. The required careful
handling of the product is conducted by the hermetic
inlet and the gentle draining of the bowl at reduced
speed. To achieve a high quality of the end product,
the sanitary equipment of the process room is
executed in the highest surface quality. Due to the
suspended vessel concept, solids handling adapted by
the customer is possible. This new centrifuge system
ensures a consistently high product quality under
economical operating conditions.
28
In certain processes, the temperature of the product
must not rise or may rise only slightly, for example
in human blood plasma fractionation using the
Cohn process. This process is characterised by the
successive precipitation of different blood proteins
in the negative temperature range. In the
development of the chamber separator for this
process, the dissipation of the individual amounts
of heat created in the separator was examined and
new cooling methods were employed. This
experience has also been applied in the new
development of the GEA Westfalia Separator hycon.
Chamber centrifuges: hundreds in operation
Fractionation by the Cohn process is executed by
reliable, cooled chamber centrifuges. These BKB
separators operate in performance ranges from 60 to
1000 l/h. They have long become established
world-wide and have proved their worth in over
400 sold machines for human blood plasma
fractionation. The compliance with a narrow
temperature range of -3 to -6 °C is important for the
process. In the clarifying separators of series BKB,
this is achieved by triple cooling: a direct bowl cooling
which extracts the heat created by air friction at the
Special Separators for Low-Temperature Applications
Always keep cool
29
outer bowl, an upper frame cooling which
extracts the heat of the cooling medium from the
bowl and a hood cooling, which extracts the
heat from the bowl top and the lock ring. The cooling
solution introduced into the cooling chambers
has a temperature of up to -20 °C, so that the outer
surfaces of the separators are completely iced
during operation. With this system, a controlled
product temperature can be achieved with a
tolerance of +/- 0.3 °C.
30
Thermal balance under control
The bowl schematic shows the main effective flows
of heat. Q in 1 is the amount of heat introduced into
the bowl by the air friction at the outer surface of the
bowl. Q in 2 is the braking effect on the bowl caused
by the inflow and outflow of the cooling liquid. Q out
1 is the amount of heat extracted by the bowl cooling.
Q out 2 is the amount of heat extracted by the frame
cooling and Q out 3 is the amount of heat extracted
by the hood cooling. The bar diagram shows the
results of measurements in a separator type BKB 28
with a 11 kW (9.3 kW) motor. The heat balances were
calculated under constant conditions. The left bar
shows the main amounts of introduced heat. The
right bar indicates the amounts of heat which can
be extracted at the lowest temperature of the cooling
medium (-20 °C). It can be seen that controlled product
temperatures can be adjusted and that cooling
can even be achieved under certain conditions
with this type of separator.
Similar heat balances can also be realized
with the hyperconcentrator through targeted
implementation of these findings in the
conceptual design of the hycon.
Feed
Clarified liquid discharge
Cooling liquid,
bowl dischargeCooling liquid, upper
frame feed
Cooling liquid, upper
frame cooling discharge
Cooling liquid, hood feed
Q in 1Q out 3
Centripetal pump
Cooling liquid,
hood discharge
Q out 2
Q out 1
Cooling liquid, bowl feed
Chamber bowl insertQ in 2
31
kW9.59.08.58.07.57.06.56.05.55.04.54.03.53.02.52.01.51.00.50.0
Heat generation Heat dissipation(maximum)
Q in Q out
Hood cooling
Frame cooling
Bowl cooling
Frictional resistance of cooling liquid discharge
Air friction on the outer bowl surface
Drive frictionGEA Westfalia Separator hycon:
the latest centrifuge technology
The latest tendency in human blood plasma
fractionation is the closed handling of the solids.
A good example of this is the hyperconcentrator
hycon with the two-room concept. It fulfils
the highest sanitary and hygiene requirements
of a machine built to GMP. A special feature
for low-temperature applications, such as
human blood plasma fractionation, is the liquid
nitrogen cooling of the bowl. Apart from the bowl
cooling, the hood and solids container cooling ensure
adequate heat extraction. It is also possible to eject
the solids into so-called endless bags for further
processing.
GEA Mechanical Equipment
GEA Westfalia Separator Group GmbH
Werner-Habig-Straße 1, 59302 Oelde, GermanyPhone: +49 2522 77-0, Fax: +49 2522 77-2828www.gea.com Th
e in
form
atio
n co
ntai
ned
in t
his
broc
hure
mer
ely
serv
es a
s a
non-
bind
ing
desc
riptio
n of
our
pro
duct
s an
d is
with
out
guar
ante
e. B
indi
ng in
form
atio
n, in
par
ticul
ar r
elat
ing
to c
apac
ity d
ata
and
suita
bilit
y fo
r sp
ecifi
c ap
plic
atio
ns, c
an o
nly
be p
rovi
ded
with
in t
he f
ram
ewor
k of
con
cret
e in
quiri
es. P
rinte
d on
chl
orin
e-fr
ee b
leac
hed
pape
r · P
rinte
d in
Ger
man
y · S
ubje
ct t
o m
odifi
catio
n · W
estf
alia
®, W
estf
alia
Sep
arat
or ® a
nd v
isco
n® a
re r
egis
tere
d tr
adem
arks
of
GEA
Mec
hani
cal E
quip
men
t G
mbH
. B_
CP-
13-0
1-00
04 E
N
GEA Group is a global engineering company with multi-billion euro sales and operations in more than
50 countries. Founded in 1881, the company is one of the largest providers of innovative equipment and
process technology. GEA Group is listed in the STOXX® Europe 600 Index.
We live our values.Excellence • Passion • Integrity • Responsibility • GEA-versity
